Review
Biol Signals Recept 2001;10:350–366
Localization, Physiological
Significance and Possible Clinical
Implication of Gastrointestinal
Melatonin
George A. Bubenik
Department of Zoology, University of Guelph, Guelph, Ont., Canada
Key Words
Melatonin W Gastrointestinal tract W
Localization W Binding sites W Ontogeny W
Phylogeny W Pathology W Motility W Food
intake W Digestion W Pineal gland W Mitosis W
Hepatobiliary system
Abstract
The gastrointestinal tract (GIT) is a major
source of extrapineal melatonin. In some ani-
mals, tissue concentrations of melatonin in
the GIT surpass blood levels by 10–100 times
and the digestive tract contributes signifi-
cantly to melatonin concentrations in the pe-
ripheral blood, particularly during the day.
Some melatonin found in the GIT may origi-
nate from the pineal gland, as the organs of
the digestive system contain binding sites,
which in some species exhibit circadian vari-
ation. Unlike the production of pineal mela-
tonin, which is under the photoperiodic con-
trol, release of GI melatonin seems to be
related to periodicity of food intake. Melaton-
© 2001 S. Karger AG, Basel
ABC 1422–4933/01/0106–0350$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Received: February 12, 2001
Accepted: May 21, 2001
in and melatonin binding sites were localized
in all GI tissues of mammalian and avian
embryos. Postnatally, melatonin was local-
ized in the GIT of newborn mice and rats.
Phylogenetically, melatonin and melatonin
binding sites were detected in GIT of numer-
ous mammals, birds and lower vertebrates.
Melatonin is probably produced in the sero-
tonin-rich enterochromaffin cells (EC) of the
GI mucosa and can be released into the por-
tal vein postprandially. In addition, melaton-
in can act as an autocrine or a paracrine hor-
mone affecting the function of GI epithelium,
lymphatic tissues of the immune system and
the smooth muscles of the digestive tube.
Finally, melatonin may act as a luminal hor-
mone, synchronizing the sequential diges-
tive processes. Higher peripheral and tissue
levels of melatonin were observed not only
after food intake but also after a long-term
food deprivation. Such melatonin release
may have a direct effect on the various GI tis-
sues but may also act indirectly via the CNS;
such action might be mediated by sympa-
Dr. George A. Bubenik
Department of Zoology, University of Guelph
Ontario, N1G 2W1 (Canada)
Tel. +1 519 824 4120, ext. 8786, Fax +1 519 767 1656
E-Mail gbubenik@uoguelph.ca
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thetic or parasympathetic nerves. Melatonin
can protect GI mucosa from ulceration by its
antioxidant action, stimulation of the im-
mune system and by fostering microcircula-
tion and epithelial regeneration. Melatonin
may reduce the secretion of pepsin and the
hydrochloric acid and influence the activity of
the myoelectric complexes of the gut via its
action in the CNS. Tissue or blood levels of
melatonin may serve as a marker of GI le-
sions or tumors. Clinically, melatonin has a
potential for a prevention or treatment of
colorectal cancer, ulcerative colitis, irritable
bowel syndrome, children colic and diar-
rhea.
Copyright © 2001 S. Karger AG, Basel
Introduction
Melatonin is a phylogenetically very an-
cient chemical, which is partly a hormone (in
humans it initiates sleep in amount smaller
than 1 mg) [1] and partly a powerful scavenger
of free radicals, an antioxidant more effective
than several well-known vitamins [2–4]. Me-
latonin crosses readily all morphophysiologi-
cal barriers, such as blood-brain barrier or pla-
centa and moves quickly into all body cells
[5]. Recently, it was confirmed that melatonin
is a significant scavenger of free radicals and
antioxidant at both physiological and phar-
macological concentrations [6]. The antioxi-
dative mechanisms of melatonin are different
from the action of other classical antioxi-
dants, such as vitamin C, E or glutathione.
Melatonin does not undergo redox cycling
and therefore it does not cause oxidation [7].
The gastrointestinal tract (GIT) is a rich
source of melatonin, surpassing substantially
the amount present at any time in the pineal
gland [8]. Whereas the nighttime plasma con-
centrations of melatonin in rats were reported
to be around 40 pg/ml, corresponding levels
Gastrointestinal Melatonin
in jejunum and ileum exceed 500 pg/g [9]. In
the quarter of century since the discovery of
melatonin in the GIT [10], a great progress
has been made in the localization and elucida-
tion of physiological functions of this remark-
able compound. Several reviews on GI mela-
tonin are available, which describe the variety
of aspects of this interesting substance [11–
16].
Localization
Melatonin, a close derivative of serotonin
(5-hydroxytryptamine [5-HT]) [17] was first
identified in the extract of the bovine pineal
gland by Lerner et al. [18]. The pineal gland is
the major source of melatonin in the peripher-
al circulation, producing melatonin in a dis-
tinct circadian fashion, with peak levels oc-
curring during the night [17]. For more than a
decade it was believed that melatonin is syn-
thesized only in the pineal gland [19]. Further
studies, however, showed that melatonin was
found to be produced in vitro in another neu-
ral tissue, the retina [20]. In the eye, melaton-
in was localized immunohistologically in cell
bodies of rods and cones [21–23] and the reg-
ulation of its synthesis and its physiological
significance were elucidated [24]. Shortly af-
ter the discovery in the retina, melatonin was
also identified in non-neural tissues, such as
the Harderian gland (HG) [22, 25, 26] and the
salivary glands of the palate [27]. As the mela-
tonin-synthesizing enzyme hydroxyindole-O-
methyltransferase (HIOMT) was also local-
ized in the pineal, retina and the HG [28], it
became obvious, that the extrapineal produc-
tion of melatonin might be more common
than was originally anticipated [29]. That as-
sumption was confirmed by reports from Rus-
sia, where Raikhlin and Kvetnoy [10] re-
ported that an extract from the mucosa of the
human appendix lightened frog skin by acting
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on dermal melanophores. The active ingre-
dient of that extract was identified by chro-
matography as melatonin and its synthesis
was assigned by immunohistology to seroton-
in-rich enterochromaffin cells (EC). In addi-
tion to the human appendix, melatonin was
also identified in the mucosa of the rabbit
intestines [30–34]. Using specific melatonin
antibodies, Bubenik et al. [35] localized mela-
tonin throughout the entire GIT of a rat.
Their study revealed that in GIT, organ and
tissue distribution of melatonin corresponds
to the localization of serotonin-producing EC
[35–37]. This finding further supported the
hypothesis that melatonin is produced in the
GI mucosa from serotonin. Subsequently, the
presence of melatonin in GIT was confirmed
by radioimmunoassay (RIA), which was vali-
dated by a high performance liquid chroma-
tography (HPLC) [38].
Numerous studies confirmed, that the day-
time melatonin concentrations in GIT tissues
are mostly 10–100 times higher than corre-
sponding melatonin levels in the peripheral
circulation [9, 39–43]. That would indicate
that either GIT has a tremendous capacity to
accumulate pineal-produced melatonin from
the circulation or more probably, that an
independent production of melatonin exists
in the GIT. Finally, because of the huge size of
the GIT, the total amount of melatonin
present at any time in the GIT of birds and
mammals (especially during the photophase)
is more than 400 times higher than the
amount of melatonin present in their pineal
glands [8, 38].
Ontogeny and Phylogeny
In the last 25 years, melatonin and mela-
tonin binding sites were identified in the GIT
of fetal and postnatal animals, ranging from
fish to humans [44–47]. Using RIA, melaton-
352 Biol Signals Recept 2001;10:350–366
in was detected in all segments of the GIT of
cow fetuses in concentrations that exceed by
several folds the levels found in the maternal
blood [48]. Postnatally, melatonin was de-
tected immunohistologically in several GI
segments of 2-days-old rat pups [49]. This
contrasts sharply with the fact that the rat
pineal does not produce substantial amounts
of melatonin-synthesizing enzyme HIOMT,
until the day 7 postnatally [50]. Those find-
ings thus indicate an extrapineal source of
melatonin in neonatal rodents. In rats, the
immunohistofluorescence indicating mela-
tonin in GIT tissues peaked around the wean-
ing time (21st day) [49]. After the initial dis-
covery of melatonin in the newborn rat, mela-
tonin was subsequently localized by RIA in
the entire GIT of newborn mice. The concen-
trations in the stomach, small and large intes-
tines were highest in the neonates and then
sharply declined, leveling at the age of 6 days
[44]. The discrepancies between melatonin
content in the GIT of neonates of different
species may be due to a different speed of
maturation and a different content of mela-
tonin in the milk, which is absorbed in the
neonates [51]. It may also reflect the differ-
ences in the activity of melatonin binding
sites, which varies substantially among spe-
cies [52]. Conversely, melatonin was detected
in the duodenum of chick embryos, which
indicates synthesis of melatonin independent
of maternal origin. Interestingly, whereas the
nighttime concentrations peaked at the day 7
of the embryonic development, the daytime
levels reached on that day their lowest point
[53]. Phylogenetically, melatonin was identi-
fied in the GIT of fishes, reptiles, amphibians,
birds and mammals, including humans [9, 42,
43, 45, 49, 52, 54].
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 Is Melatonin Independently
Synthesized in the GIT or Is It
Pineal-Derived?
As an injection or an alimentary adminis-
tration of exogenous melatonin and its pre-
cursor tryptophan resulted in a significant ac-
cumulation of melatonin in the GIT [39, 49,
55–57], it was initially questioned whether
the presence of melatonin in the digestive sys-
tem is due to its accumulation from the circu-
lation (particularly during the night) or due to
an independent synthesis in situ [49]. A sig-
nificant diurnal variation of melatonin con-
centrations in some GI tissues (with plasma
concentration much higher during the night)
was reported by several authors in intact ani-
mals, mostly birds [52, 58–60]. Conversely, in
rats pinealectomy (Px) reduced melatonin lev-
els in serum but not in the GI tissues [9]. In
pigeons, Px decreased midnight concentration
of melatonin in plasma by some 50% but did
not decrease midday melatonin levels [58].
Whereas Px did not influence an immediate
midnight concentration of melatonin in the
duodenum or the eyes two weeks after the
operation, tissue concentration in the HG in-
creased to 64% of the amount detected in the
sham operated birds, thus indicating a com-
pensatory increase of melatonin in the HG.
Based on these results it was concluded that
an increase in plasma concentrations of mela-
tonin is due to the elevation of its extrapineal
production, mostly in the HG [58]. A postop-
erative increase of melatonin was also re-
ported in plasma of Px sheep [61]. Conversely,
no diurnal differences in melatonin levels
were observed in immunohistological studies
performed in intact or pinealectomized rats
[49]. The last finding would indicate that the
nighttime increase of melatonin reported in
some studies in the GIT of intact animals is
caused by accumulation of pineal-derived me-
latonin from the blood. Indeed, the newest
Gastrointestinal Melatonin
studies of Huether et al. [62] and Messner et
al. [63] indicate that GIT may act as a sink for
pineal-derived melatonin, especially during
the night. Differential results of studies inves-
tigating the rhythm of GIT melatonin and the
effect of Px on such rhythms may be related to
differential feeding and digestive strategies
[41, 42]. Accumulation of pineal-derived me-
latonin in GIT tissues is highly probable. Mel-
atonin binding sites were identified in the
entire muscular stroma of the human fetal
GIT as well as in the GIT of deer fetuses [46,
47]. Furthermore, melatonin receptors or
binding sites were found in many segments of
the GIT of various birds and mammals, in-
cluding humans [9, 52, 64–68]. Although
binding site parameters exhibited diurnal
variation in some species, this was not con-
firmed in others [52, 54, 69]. In addition,
large variations of melatonin concentrations
in the individual segments of the GIT were
found among many species of birds and mam-
mals [9, 35, 38, 44, 57, 64, 66, 68–70]. Often,
these tremendous variations of melatonin
concentrations in GIT tissues appears to be
related to food intake rather than to photoper-
iodicity as is the case of pineal-produced me-
latonin [41, 70, 71]. In that case, the reported
differences among species may reflect the fact
that some animals are diurnal whereas others
are nocturnal. In addition, some animals are
monophasic and others are polyphasic feed-
ers. Finally, different type of digestion occurs
in monogastric, as compared to polygastric
(ruminant) animals [16, 42, 72].
Melatonin Synthesis and Secretion
Although a direct synthesis of melatonin in
the GIT has not yet been demonstrated in
vitro, an independent production of melaton-
in in the GIT was indirectly indicated in sev-
eral studies. Two enzymes, synthesizing mela-
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tonin from serotonin, the rate limiting en-
zyme N-acetyltransferase (NAT) and the
terminal enzyme, hydroxyindole-O-methyl-
transferase (HIOMT) were detected in the GI
tissues, [11, 73–75]. Histological studies indi-
cated that melatonin is synthesized in the
serotonin-rich enterochromaffin cells of the
mucosa [12, 30, 35]. Whereas Px attenuated
nighttime levels of melatonin in blood, it did
not affect daytime levels [61, 76], which are
probably produced in the GIT [39, 71, 77].
That GIT is a major contributor to daytime
levels of peripheral concentrations of mela-
tonin in fish was demonstrated by Kezuka et
al. [78]. As they detected melatonin in plasma
of goldfish after Px and bilateral enucleation,
they concluded that these residual levels are
of GI origin. In addition, further studies re-
vealed that Px did not abolish presence of
melatonin in the GI tissue of mammals [9, 38,
39, 49, 77]. Furthermore, melatonin concen-
trations increased in human and rat peripher-
al blood after tryptophan (TRP) administra-
tion. Similarly, elevated melatonin levels
were also detected in Px rats fed exogenous
TRP. That TRP-increased plasma levels were
higher after oral as compared to intraperito-
neal administration and the melatonin eleva-
tion did not occur in animals with the ligature
of the portal vein indicated an independent
production of melatonin in the GIT [39, 77,
79, 80]. In the study of Ozaki and Lynch [81],
Px did not abolish substantial daytime levels
of melatonin in plasma, as long as animals
were fed ad libitum. However, these levels
disappeared when food was restricted. Fur-
thermore, the findings that melatonin levels
were higher in the portal vein than in the sys-
temic circulation and that the TRP-induced
elevation in the portal vein occurred earlier
than in the systemic circulation also demon-
strated that GIT contributes significantly to
circulating plasma levels of melatonin, espe-
cially during the daytime [8, 54, 59, 71, 79].
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Conversely, impaired degradation of mela-
tonin in the liver, markedly increased mela-
tonin concentration in the peripheral blood of
cirrhotic patients [82, 83].
Whereas tryptophan administration in-
creased melatonin levels in the GIT of Px
chickens, [39, 77] similar tryptophan loading
did not alter melatonin levels in the GIT of
intact chickens [84]. This may indicate, that
in intact birds the availability of melatonin
precursor tryptophan is not essential for the
modulation of melatonin levels. Finally, GIT
derived melatonin may be most active in an
autocrine or a paracrine fashion [12, 52, 66]
acting on the binding sites in the various seg-
ments of the GIT [16, 66, 68].
The newest study indicates that melatonin
may perhaps act as a luminal hormone, parti-
cipating in the sequential activation of diges-
tive processes [42]. Melatonin detected in the
liquid of the GIT lumen might have been
released from some melatonin rich food [7,
85]. Although Hattori et al. [86] demonstrated
that in chickens, melatonin-rich food could
elevate blood levels of melatonin, the correla-
tion between concentrations of melatonin in
the porcine luminal fluid and mucosa indi-
cates that a substantial amount of luminal
melatonin in mammals is probably of muco-
sal origin or it is produced by the gastrointesti-
nal microflora [42]. Another possible source
of luminal melatonin could be bile, where
substantial concentrations of melatonin were
reported [54, 87]. (For details see Melatonin
and the Hepatobiliary System.)
Tissue Localization and Action
Using immunohistology or RIA, melaton-
in was localized mostly in the mucosa of the
GIT [10, 35, 42, 49, 52, 54, 66]. Similarly,
using autoradiography, maximal binding of
melatonin was also observed in the mucosa
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and the intestinal villi [52, 66]. Conversely,
lower concentration of melatonin and less
binding was detected in the submucosa and
muscularis [12, 42, 49, 52, 65, 66]. These find-
ings would support the speculation, that mela-
tonin is produced by EC in the mucosa but
can act as a paracrine hormone in other seg-
ments of the GIT [12]. That substantial
amount of melatonin was detected in the mus-
cularis (in some organs there was as much
melatonin in the muscularis as was in the
mucosa) [42, 49] indicates, that perhaps mela-
tonin produced in the mucosa may also act
either on smooth muscles of the muscularis or
on the myenteric nervous system, as suggested
by Barajas-Lopez et al. [88]. The nervous
plexus of Meissner is located in the intestinal
submucosa, whereas the Auerbach plexus is
located between the inner circular and outer
longitudinal layer of the gut musculature.
Therefore, melatonin could easily move from
the mucosa into deeper layers via numerous
blood vessels present in the lamina propria
and submucosa. Whether parasympatical
nerves play any role in the synthesis of mela-
tonin in the GIT is uncertain. Bilateral vagot-
omy had no effect on the tissue concentration
of melatonin in the GIT of quails (Bubenik
and Zeman, unpubl. obs.). Conversely, a lo-
calization of melatonin binding sites in the
intestinal villi [52] may indicate the role of
melatonin in the intestinal epithelium, per-
haps in the transmembrane transport of ions
and electrolytes, as demonstrated by Legris et
al. [89]. In intact mice, melatonin treatment
increased water content in their feces [44],
thus supporting the above-mentioned finding
of Legris et al. In addition, melatonin may
play a role in the regulation of colonic Cl –
secretion via melatonin receptors. Basolateral
and apical application of melatonin stimulat-
ed short-circuit current of human colonic T84
cells in a dose-dependent manner [90]. At
the subcellular level, melatonin binding was
Gastrointestinal Melatonin
strongest in the nuclear fraction, to be fol-
lowed by the microsomial, mitochondrial and
cytosolic fractions [12, 72]. It appears that the
extranuclear 2-[125I]iodomelatonin binding
sites are localized in the membrane, thus indi-
cating that melatonin receptors are linked to
G-proteins [91].
Melatonin and Food Intake
Mounting evidence indicates that there is a
relationship between melatonin and food in-
take. Melatonin implants increased food in-
take in mice [43]. Several other studies found
a temporary increase of melatonin concentra-
tions in blood of animals re-fed after a period
of fasting [41, 56, 59]. A similar elevation of
blood concentrations of melatonin was re-
ported in human saliva after an evening meal
[92]. When men were fed slow-release prepa-
ration of melatonin, mean melatonin levels in
plasma were significantly higher in fed than in
the fasted state [93]. The rapid increase of
melatonin in blood after re-feeding [41] may
constitute the speculative pulse that causes
the shift in biological rhythms. Changes in
locomotion, temperature and cortisol rhythm
were reported after food intake. This shift of
rhythms was not mediated by the pineal
gland, as it was not abolished by lesions in the
suprachiasmatic nucleus, the brain tissue that
regulates the circadian rhythm of melatonin
synthesis in the pineal [94]. Similarly, feeding
entrains an endogenous rhythm of swimming
in the blind Mexican cavefish. Finally, re-
stricting food intake only to the light period of
the day changed significantly the sleep pattern
in rats. Conversely, Px or sham Px had no
effect on the reported change in the sleep pat-
tern, thus indicating an effect independent of
the pineal gland [96]. All these changes in the
circadian activity related to food intake could
be explained by a pulse of melatonin released
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from the GIT, that first enters peripheral cir-
culation and then alters the circadian clock
[39, 41]. In humans, the sudden elevation of
melatonin concentrations in blood may also
be the cause of sleepiness experienced after
midday meals [71] and be the reason for the
popularity of ‘siesta’, the early afternoon nap-
ping period. A short pulse of melatonin se-
creted into circulation in midday may also
help to cool down the body temperature [97].
The well-established hypothermic effect of
melatonin is mostly dose-dependent [98] and
can be manipulated by light [99]. It can be
therefore speculated that because of the hypo-
thermic effect, siesta is most popular in the
hot regions of the globe.
Melatonin and Digestive Processes
Earlier studies revealed that melatonin
could influence the peristalsis of GIT muscles
in vitro and in vivo [100–106]. Subsequently
it was demonstrated that food restriction de-
creased melatonin concentration in the pineal
but increased melatonin levels in plasma
[107] and in the GIT (in some segments by as
much as 2–7 times) [59, 70]. This indicated,
that the surplus of circulating melatonin was
derived from the GIT tract. Reduction of
caloric intake or an administration of mela-
tonin increased the life span of mice [108].
The increase in longevity reported in animals
on low-calorie diet may be due to the eleva-
tion of GIT melatonin observed in food-
deprived animals [70, 109]. As melatonin pro-
tects the organism against hydroxyl-radical-
mediated oxidative damage [5], it was hy-
pothesized that the age-related decline of me-
latonin is partly responsible for the aging pro-
cess [110, 111]. It can be speculated that the
reduction of food intake increases the produc-
tion of melatonin in the GIT, which in turn
elevates circulating levels of melatonin to con-
356 Biol Signals Recept 2001;10:350–366
centrations observed normally only in much
younger animals [59, 70].
Melatonin and the Hepatobiliary
System
The liver is the major organ responsible for
melatonin degradation [15, 112]. A previous
study indicated that 92–97% of melatonin is
metabolized on a single pass through the liver
[113]. Although this has not been confirmed
in a more recent experiment [71], liver degra-
dation to 6-hydroxymelatonin remains the
major metabolic pathway for melatonin deac-
tivation [114]. Interestingly, recent studies of
Huether et al. [62] indicate that below a cer-
tain threshold (day-time melatonin concen-
trations in plasma) melatonin escapes liver
metabolism; above that threshold, melatonin
is quickly metabolized.
Initially, immunohistological investigation
did not detect melatonin in liver tissues [35],
but later studies revealed melatonin in the
nuclei of hepatic cells [72]. Most recently,
melatonin has been identified in the human
liver tissues in concentrations 15 times higher
than levels detected in plasma [53]. That GIT
melatonin contributes to the peripheral circu-
lation via portal vein has been documented
above (see Melatonin Synthesis). Several oth-
er studies indicate the importance of a sub-
stantial degradation of melatonin during the
liver passage. Portocaval anastomosis, which
bypasses the flow of melatonin through the
liver, disrupts circadian locomotor activity
and pineal melatonin rhythms in rats [115]. In
addition, disruption of diurnal sleep rhythms
was reported in human patients suffering
from liver cirrhosis [82, 116]. Such distur-
bances are probably the result of an insuffi-
cient metabolism of melatonin in the cirrhotic
liver as reported by Steindl et al. [83]. In view
of these reports, it can be hypothesized that a
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large increase of melatonin concentrations in
peripheral blood, originating in the GIT and
escaping liver degradation, may result in the
postprandial sleepiness, which in some cases
may disrupt the circadian rhythm.
Recently, melatonin was detected by RIA
and verified by HPLC in bile samples from
gallbladders of various mammals including
humans in concentrations ranging from
2,000–11,000 pg/ml [87]. These levels are by
far the highest melatonin concentrations
found in any segment of the GIT. They exceed
daytime serum levels by 2–3 orders of magni-
tude [87] and are 10–40 times higher than
melatonin levels found during the photophase
in the pig and cow GIT mucosa and muscula-
ris (50–900 pg/g) [42]. The authors hypothe-
sized that high levels of melatonin in bile may
prevent oxidative damage to the mucosa of
the biliary tract and the epithelium of the
intestine caused by bile acids and oxidized
cholesterol derivatives [87]. Conversely,
Messner et al. [53] found much lower mela-
tonin levels in non-concentrated human bile
taken from the bile duct. Their bile concentra-
tions of melatonin (85 pg/ml) correlated well
with levels found in plasma (55 pg/ml). The
authors calculated that a substantial amount
of melatonin (approximately 51 ng/24 h) is
excreted into the gut via the bile duct and they
concluded that melatonin might act as a me-
diator of inter-organ communication between
gut and liver. Although, it can be hypothe-
sized that bile contributes significantly to con-
centrations of luminal melatonin, research
studies in cows and pigs revealed completely
opposite results between these two species.
Whereas in cows concentrations of luminal
melatonin in jejunum were the lowest of all
GI segments, in pigs the levels were the high-
est [42]. The outcome may reflect the differ-
ent digestive strategies of mono- and polygas-
tric species.
Gastrointestinal Melatonin
Melatonin and GIT Motility
A decade before the detection of melatonin
in the GIT, Quastel and Rahamimoff [100]
demonstrated that high concentrations of me-
latonin inhibit spontaneous and serotonin-
induced contraction of rat duodenum in vitro.
Similar relaxations of smooth muscles after
melatonin administration were also observed
in the uterus [117]. In addition, muscles of the
tail and brain arteries in rats also exhibited
contractile response to melatonin [118, 119].
Similar action on muscles was also reported
for the smooth muscles of the GIT. In vitro,
high concentrations of melatonin inhibited
spontaneous and 5-HT-induced peristalsis of
the stomach [101, 102], ileum [103], jejunum
and colon [104] muscles. These studies re-
vealed that the GIT tissues with the greatest
responsiveness to melatonin were the seg-
ments exhibiting the highest concentration of
this indole [45]. Early studies demonstrated
that melatonin is acting through a different
mechanism than the adrenaline and acetyl-
choline system. Blockade of serotonin recep-
tors indicated that melatonin is not acting as
antagonist of 5-HT stimulatory receptors but
rather as an agonist of 5-HT inhibiting neural
receptors [103]. Few years ago, Barajas-Lopez
et al. [88] studied the modulatory effect of
melatonin on the enteric nervous system.
Their studies indicated that melatonin inhib-
its gut muscles directly by inhibiting specifi-
cally nicotinic channels. In addition, Reyes-
Vasquez et al. [120] reported that melatonin
might interact with apamine-sensitive, possi-
bly Ca++-activated K+ channels. That observa-
tion was recently supported by Storr et al.
[121] who reported that an inhibition of small
conductance K+-channels attenuated mela-
tonin-induced relaxation of rat gastric mus-
cles contracted by serotonin. Finally, recently
melatonin was found to potentiate the ampli-
tude and frequency of spontaneous contrac-
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tions in quail caecal smooth muscles. In con-
trast to melatonin, these contractions were
completely blocked by adrenaline [122].
In addition to in vitro effect, melatonin
was also found to modify the serotonin-
induced contraction in vivo. Whereas in vi-
tro, the maximal inhibition of the 5-HT-
induced spasm was achieved when the con-
centration of melatonin was 50–100 times
higher than the concentration of serotonin, in
vivo the effect was observed at the concentra-
tion of only 1:1. That indicated that in vivo
extraintestinal mechanisms (perhaps involv-
ing the pineal gland or CNS) might be in-
volved. The participation of CNS in the gut
peristalsis, perhaps via cholecystokinin was
indicated by Benouali-Pellissier [123]. Addi-
tional studies, investigating serotonin and
melatonin levels after 5-HT and melatonin
implants and an administration of p-chloro-
phenylalanine (a blocker of serotonin-synthe-
sizing enzyme) indicated possible feedback
mechanisms [44]. These findings let us hypo-
thesize that a mutually counterbalancing sys-
tem exists between serotonin and melatonin,
regulating their levels in the GIT [44]. Al-
though in vivo, melatonin injections reduced
the facilitation of food transit time, which was
achieved in 5-HT-implanted mice; melatonin
given to intact animals decreased food transit
time, albeit not to the same extent as 5-HT
[105, 106]. This was the first report indicating
that in addition to the inhibitory effect on 5-
HT-induced contractions, melatonin may
have a stimulatory effect on the smooth mus-
cles of the GIT tract. Two other findings sup-
ported such a stimulatory effect of melatonin.
Using in vivo electromyography, Benouali-
Pellissier [123] demonstrated that the sup-
pression of regular spiking activity observed
in the ileum of Px rats was restored by mela-
tonin. Her studies indicated that melatonin is
involved in the modulation of cholecystoki-
nin action on ileal motility via CNS [123].
358 Biol Signals Recept 2001;10:350–366
Acceleration of food transit time (FTT) in
melatonin-treated rats was also reported by
Martin et al. [13]; interestingly, they found
the acceleration of FTT only in fed rats but
not in the fasting ones. Most recently, it was
reported that high doses of melatonin appear
to inhibit the spontaneous or serotonin-in-
duced contraction of GIT muscles by Ca++-
related, K+ channel-mediated mechanism and
to induce gut elongation. Conversely, low
doses of melatonin exerted stimulatory effect
on the gut musculature, leading to gut short-
ening [124]. Most recent receptor studies re-
vealed that the most likely sites of melatonin
action in smooth muscles of the GIT tract are
the ML2 receptors [125]. In rats, an endoge-
nous melatonin produced a pharmacological
effect on pre- and postprandial intestinal mo-
tility. The effect, the inhibition of irregular
spiking activity and a reinforcement of the
migrating motor complexes, was observed
only at night, when melatonin levels in blood
are high [126].
Melatonin and Mitosis
A biphasic mitotic activity within a 24 h
period was reported in the duodenum and
colon of mice. Exogenous application of mela-
tonin substantially influenced this mitotic ac-
tivity in the alimentary canal [127, 128]. Pi-
nealectomy increased the mitotic index in the
rat intestinal crypts [129]. Callaghan [130,
131] reported that the hyperproliferative ef-
fect of Px may be mediated by the vagal and
sympathetic innervation of the gut and that it
can last as long as 6 months. In another study,
melatonin was found to reduce the prolifera-
tion of jejunal epithelium in mice [132], but
melatonin given alone did not influence mi-
totic activities in the gastric mucosal epithe-
lium of rats [133]. Conversely, an opposite
effect, an inhibition of cell proliferation in the
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GIT after Px was reported by Pawlikowski
[134]. Similarly, a single injection of melaton-
in stimulated cell division in duodenal epithe-
lium of intact mice [135]. Finally, administra-
tion of melatonin, injected intraperitoneally,
facilitated the regeneration of goblet cells in
the colonic epithelium of mice suffering from
experimentally induced colitis [136]. Whereas
low doses of melatonin (1–10 Ìg/mouse) de-
creased mitotic activity in the rat jejunal epi-
thelial cells, high doses (100 Ìg/mouse) had
the opposite effect; it increased mitosis [137].
In view of the above-mentioned studies, it can
be speculated that the different results found
by different groups could be due to variations
of doses used and GIT organs investigated.
Opposite effects of various melatonin doses
on several other functions of the GIT are dis-
cussed in the section ‘Dual Effects of Mela-
tonin’.
Melatonin and GIT Pathologies
Ulcers and Colitis
Early studies indicated that melatonin has
a protective effect on the development of gas-
tric ulcers [138, 139]. However, only more
recently, this phenomenon has been investi-
gated in more detail. In rats, melatonin pre-
vented stress and ethanol-induced gastric le-
sions, presumably by counteracting the 5-HT-
induced reduction in the blood flow [138–
140]. Bubenik and coworkers reported reduc-
tion in the incidence and severity of gastric
ulcers in pigs after administration of melaton-
in mixed in food. They reported that a highest
incidence of gastric ulcers in young pigs was
associated with the lowest concentrations of
melatonin in their blood and stomach tissues
[58, 141]. Melatonin and its precursors L-
tryptophan protected against gastric isch-
emia-reperfusion injuries in rats [80, 142].
Two studies indicated that the protection
Gastrointestinal Melatonin
against stress-induced gastric lesions is due to
a prostaglandin-mediated mechanism [80,
143]. The protection against stress-induced
and ischemia-induced lesions is mediated by
the scavenging of free oxygen radicals and the
restoration of mucosal microcirculation [144–
146]. A dose-dependent increase of superox-
ide bismutase and glutathione reductase and a
decrease of xantine oxidase observed after
melatonin treatment contributed to the pro-
tection of gastric mucosa against damage
caused by ischemia-re-perfusion. A signifi-
cant reduction of exfoliation of superficial
mucosal cells and a decrease of white blood
cell infiltration was observed after melatonin
treatment [147]. In another study, exogenous
melatonin reduced plasma but not gastric tis-
sue concentrations of malondialdehyde, a lip-
id peroxidation product [148]. A similar
mechanism, an antioxidative effect of mela-
tonin, may also apply in the preventive and
therapeutic effects of this indole on experi-
mentally induced colitis. That effect may be
combined with improved microcirculation
and the stimulation of epithelial proliferation
[136]. Finally, the studies of Kato et al. [149]
suggest that CNS may mediate the protective
anti-stress action of melatonin in gastric mu-
cosa; intracisternally injected melatonin de-
creased the secretion of hydrochloric acid and
pepsin in the rat stomach. Conversely, the
protection to GI mucosa may be partly due to
its effect on mitotic activity [136, 137], which
may be mediated via specific gastrin receptors
[133]. The remarkable effect of intraperitone-
ally administered melatonin on the regenera-
tion of intestinal mucosa, and cessation of
occult bleeding, loss of weight and diarrhea,
all resulting from dextran-sodium sulphate in-
duced colitis, may be due to its antioxidative
effect [5], improvement of microcirculation
[145] or due to the stimulation of the immune
system [16, 150]. High affinity melatonin
binding sites were located in the mucosa of
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the appendix [69] and the number and the
size of Payer’s patches (the major lymphatic
tissue of the GIT tract) increased substantially
after melatonin treatment [151].
Irritable bowel syndrome: (IBS), is a GI
disease whose symptoms improve at night
and are more pronounced in shift workers.
Therefore, this affliction was chosen as a can-
didate for treatment with melatonin [16]. In
the first preliminary clinical trials, the symp-
toms for IBS improved in female patients suf-
fering from IBS and a larger clinical study is
now in progress in Singapore (Wei Zhen Lu,
pers. commun.). Most recently, melatonin sig-
nificantly reduced bloody diarrhea and loss of
body weight in rats with dinitrobenzene sul-
fonic acid-induced colitis. These effects were
accompanied by a remarkable improvement
of colonic microstructure as well as a signifi-
cant decrease of colonic myeloperoxidase and
malondialdehyde [152].
Colic
Melatonin may act as a natural inhibitor of
serotonin and a mutual feedback between
these two indoleamines may exist [44]. The
disruption of balance between these two
chemicals may be the cause of a painful ab-
dominal affliction known as colic, which af-
fects a substantial proportion of human in-
fants. As colic is mostly found in very young
children, in which melatonin levels are low, it
was speculated that colic is caused by an
imbalance between 5-HT and melatonin
[153]. Once the melatonin levels increase
(usually within the first 3 months) the colic
disappears [154].
Cancer
Melatonin may serve as a marker of GIT
cancer. Melatonin exhibited inhibitory effect
on intestinal carcinogenesis induced in rats by
dimethylhydrazine (DMH) in rats [155]. Se-
rum melatonin levels in rats in which colon
360 Biol Signals Recept 2001;10:350–366
tumors were induced by DMH were in-
creased, but no diurnal variation was ob-
served, as compared to controls. The number
of melatonin-containing cells was decreased
in all tissues studied (stomach, duodenum,
ileum and descending colon). Conversely,
DHM + melatonin treatment increased the
number of M-containing cells in the stomach
and duodenum, albeit not to the same level as
seen in controls [156]. Carcinomas of de-
scending colon were observed in 65% of rats
treated simultaneously with melatonin and
DMH, as compared to 100% incidence of
tumors observed in rats treated with DMH
alone [157]. In healthy human subjects, night-
time melatonin levels in plasma were higher
than the daytime levels. In patient with gastric
and intestinal cancers, the circadian concen-
trations of melatonin were reversed [158]. Au-
thors speculated that an extrapineal produc-
tion of melatonin was the cause of this dis-
crepancy.
In humans higher nighttime melatonin
concentrations in plasma were detected in
both control and colorectal patients. In cancer
patients the nighttime concentrations were in
the same range as those of controls whereas
the daytime concentrations were significantly
higher. Surgical treatment of the colorectal
carcinoma increased blood levels of melaton-
in during the night but the post surgical
increase was more pronounced in patients
with metastases [43]. Authors speculated that
melatonin might play a protective role in the
development of colorectal cancer by stimula-
tion of the immune system [150, 151]. Re-
viewing the current literature, Fraschini et al.
[159] concluded that melatonin is a natural
oncostatic agent. In addition to acting directly
on immune cells, melatonin may act as an
arm of the circadian clock, giving a time-relat-
ed signal to various body functions and thus
affecting the timing and quality of the im-
mune response [160].
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 Diarrhea
Because of its action on electrolyte trans-
port [89, 90] and the influence on the water
content in feces [44], melatonin might be con-
sidered as an effective remedy in the treat-
ment of severe diarrhea.
Dual Effects of Melatonin
On several occasions, melatonin adminis-
tration has been reported to have an opposite
effect on various physiological processes, such
as mitosis [127, 128, 134–137], peristalsis or
food transit time [100, 103, 105] or the change
in the length of the intestines [124], depend-
ing on the concentration or the route of ad-
ministration. These results may indicate that
physiological or pharmacological doses may
significantly differ in their effects. Some may
act directly in the endocrine, paracrine or
autocrine fashion, others may be mediated
via CNS or via various neuromodulators,
such as substance P, nerve growth factor, gas-
trin, cholecystokinin or other neurotrophic
hormones [12, 15, 49, 123, 133].
Conclusion
Substantial evidence indicates that mela-
tonin is produced in the GIT of most verte-
brate species. Circadian variation of GI mela-
tonin appears to be controlled not by a photo-
periodicity (like the pineal gland) but by a spe-
cies-specific periodicity of food intake. Mela-
tonin might be involved in the modulation of
GI motility, regulation of mucosal water and
ion transport. Melatonin may also modulate
epithelial proliferation, sequential activation
of GIT during the postprandial transport of
food, and the initiation of the transient sleep-
ing period following food intake. Finally, me-
latonin may be essential in the prevention of
mucosal lesions by increasing blood supply.
Melatonin also exhibits a powerful antioxi-
dant action and can stimulate mitosis. It is
also involved in the CNS-mediated effects on
the gut myoelectric complex and on the gas-
tric secretion of pepsin and hydrochloric acid.
Clinically, melatonin should be considered
for prevention or a treatment of colorectal
cancer, gastric ulcers, ulcerative colitis, irrita-
ble bowel syndrome, children’s colic and se-
vere diarrhea.
Acknowledgements
I would like to thank all my collaborators who
helped me in studies I have performed in the last 25
years, particularly GM Brown, who introduced me to
the topic of melatonin and has remained my closest
collaborator ever since. In addition, I am indebted to
my most involved collaborator, Shiu-Fun Pang, whose
contributions were essential in realization of many cru-
cial experiments. Furthermore I would like to thank
Bob Purtill, Ron Ball, Roger Hacker, Peter Smith,
Ludek Bartos, Len Niles, Lee Grota, Patty Pentney
and Savita Dhanvantari for taking part and helping me
to perform many of my melatonin studies.

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